Major depressive disorder (MDD) is prevalent, debilitating, and costly both to individuals and society. One of the challenges with this heterogeneous syndrome is our inability to identify clinically and biologically distinct subsets of patients and so treatment assignment is fairly arbitrary. A second problem we face is that the majority of antidepressant medications share a common mechanism of action: modulation of monoamine systems. Thus, it is not surprising that the overall remission rate to initial therapy can be as low as 33%. These facts suggest that we should reconceptualize our approach to the treatment of MDD. We need to move toward individualized MDD treatment strategies by identifying more homogenous cohorts of patients who are responsive to specific antidepressant therapies. Omega-3 polyunsaturated fatty acids (n-3 PUFA) are a focus of treatment research for many medical and psychiatric disorders. One rationale that could explain therapeutic benefit across a wide array of syndromes is the observation that increasing n-3 PUFA levels shift the production of eicosanoids away from the arachidonic acid, pro-inflammatory, cascade and toward the production of anti-inflammatory metabolites. And so, individuals who manifest inflammation as a component of their illness might benefit from an n-3 PUFA intervention. Although studies in subjects with MDD suggest that n-3 PUFA may be a beneficial adjuvant therapy with traditional antidepressant medications, most monotherapy trials find, at best, a small effect size benefit for n-3 PUFA in heterogeneous samples of subjects with MDD. Work from our previous R-01 identified a homogeneous set of subjects with MDD who were particularly responsive to the n-3 PUFA eicosapentaenoic acid (EPA): subjects with MDD who had multiple biomarkers indicating high inflammation. The one clinical characteristic correlated with the presence of high inflammatory markers was obesity (BMI >30). In fact, 48% of our obese subjects with MDD (vs. 11% in our normal weight group) had baseline levels of high sensitivity C-Reactive Protein (hs-CRP) > 3 mg/l, the accepted cut-point for defining high inflammation. All of the obese subjects with high hs-CRP met criteria for high inflammation on multiple additional markers of inflammation. The overall aim of this application is to extend our previous findings by performing a definitive clinical trial: We propose a 150-subject, two-site, 8-week double-blind randomized trial investigating the efficacy of a 1000 mg/day of EPA-enriched PUFA monotherapy vs. placebo in subjects with MDD, obesity, and baseline levels of hs-CRP > 3 mg/l. We will test 1 primary efficacy hypothesis, 2 mediator hypotheses, and 2 exploratory hypotheses. Successful completion of this R-01 will have significant public health consequences: (1) we will identify a cohort of patients with MDD who are likely to respond to treatment with a relatively benign natural product; (2) we will provide the first test of one potential mechanism responsible for the antidepressant effect of n-3 fatty acids; and (3) we will advance the concept of personalized medicine in the field of psychiatry.